In this project we will test the hypothesis that pharmacological targeting of kainate receptors, a family of ionotropic glutamate receptors, represents a viable therapeutic strategy in an animal model of multiple sclerosis (MS). Glutamate receptor activation contributes to excitotoxic degeneration of oligodendrocytes that occurs in diseases of aberrant myelination, such as MS. Oligodendrocytes and their progenitor cells express all three types of ionotropic glutamate receptors (AMPA, kainate, and NMDA subfamilies), with each appearing to play a distinct role in mediating degeneration in models of glial excitotoxicity. Kainate receptor activation, in particular, produces toxicity through at least two distinct mechanisms, calcium-mediated excitotoxicity and priming of oligodendrocytes to complement attack, suggesting that these receptors could play a prominent role in oligodendrocyte death prevalent in MS. Broad-spectrum AMPA/kainate receptor antagonists are efficacious in animal models of MS, ameliorating disease in mice with experimental autoimmune encephalomyelitis (EAE), and reducing physiological measures of ischemic damage in cortical oligodendrocytes when combined with non-competitive NMDA receptor antagonists. Inhibition of AMPA and NMDA receptors, however, has proven clinically problematic. In contrast, subtype-selective antagonists of kainate receptors are well tolerated in animal models and preclinical studies, but these have not been tested in animal models of MS. Furthermore, it is unclear what subtype of kainate receptors are critical for oligodendrocyte excitotoxicity. This is a particularly important question because the subunit composition of native kainate receptors will determine their sensitivity to selective antagonists. In this exploratory study, we will test our central hypothesis first by defining the contribution of specific receptor subunits to spinal oligodendrocyte excitotoxicity using gene-targeted mice and selective pharmacological tools. Secondly, we will test if progression of experimental autoimmune encephalomyelitis (EAE), a mouse model of MS, is attenuated by kainate receptor antagonists or in kainate receptor knockout mice. These experiments will enable us to definitively assess whether targeting of kainate receptors represents an approach with therapeutic potential in treatment of MS. PUBLIC HEALTH RELEVANCE In this project we will test the hypothesis that inhibition of kainate receptors represents a viable strategy for slowing disease progression in an animal model of multiple sclerosis. Kainate receptors comprise a family of proteins responding to the excitatory neurotransmitter L-glutamate;these receptors in part mediate excitotoxic death of oligodendrocytes, which are glial cells in the brain required for normal neuronal function. To test our hypothesis we will utilize newly developed selective pharmacological agents and gene-targeted mice lacking kainate receptor subunits.